No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples

Abstract

Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified eighteen candidate genes for depression studied ten or more times and examined evidence for their relevance to depression phenotypes. Utilizing data from large population-based and case-control samples ( n ranging from 62,138 to 443,264 across subsamples), we conducted a series of preregistered analyses examining polymorphism main effects, polymorphism × environmental moderator interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity). There was no clear evidence for any candidate gene polymorphism associations with depression phenotypes or any polymorphism × environmental moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than noncandidate genes. We demonstrate that phenotypic measurement error is unlikely to account for these null findings. Our results do not support previous depression candidate gene findings, wherein large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, our results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.